Medical and Surgical Treatment of Reproductive Outcomes in Polycystic Ovary Syndrome: An Overview of Systematic Reviews

Polycystic ovary syndrome (PCOS) is a common, complex condition that affects up to 18% of reproductive- aged women, causing reproductive, metabolic and psychological dysfunctions. We performed an overview and appraisal of methodological quality of systematic reviews that assessed medical and surgical treatments for reproductive outcomes in women with PCOS. Databases (MEDLINE, EMBASE, CINAHL PLUS and PROSPERO) were searched on the 15th of September 2017. We included any systematic review that assessed the effect of medical or surgical management of PCOS on reproductive, pregnancy and neonatal outcomes. Eligibility assessment, data extraction and quality assessment by the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool were performed in duplicate. We identified 53 reviews comprising 44 reviews included in this overview; the majority were moderate to high quality. In unselected women with PCOS, letrozole was associated with a higher live birth rate than clomiphene citrate (CC), while CC was better than metformin or placebo. In women with CC-resistant PCOS, gonadotrophins were associated with a higher live birth rate than CC plus metformin, which was better than laparoscopic ovarian drilling (LOD). LOD was associated with lower multiple pregnancy rates than other medical treatments. In women with PCOS undergo- ing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), the addition of metformin to gonadotro- phins resulted in less ovarian hyperstimulation syndrome (OHSS), and higher pregnancy and live birth rates than gonadotrophins alone. Gonadotrophin releasing hormone (GnRH) antagonist was associated with less OHSS, gonadotrophin units and shorter stimulation length than GnRH agonist. Letrozole appears to be a good first line treatment and gonadotrophins, as a second line treatment, for anovulatory women with PCOS. LOD results in lower multiple pregnancy rates. However, due to the heterogeneous nature of the included popula- tions of women with PCOS, further larger scale trials are needed with more precise assessment of treatments according to heterogeneous variants of PCOS.


Introduction
Polycystic ovary syndrome (PCOS) is one of the most important dilemmas in reproductive medicine. PCOS is a member of the World Health Organization group II ovulation disorders, and has a 9-18% prevalence among reproductive-aged women (1) and nearly 80% among infertile anovulatory women (1,2). There is an ongoing debate related to its definition, aetiology, diagnosis and treatment for its clinical phenotypes (3). Since first described by Stein and Leventhal (4), a number of reports and meetings have suggested diagnostic criteria for this condition (3,5,6). However, the criteria reported by ESHRE/ASRM in Rotterdam in 2003 are most com-monly used both in research and clinical care. These criteria propose that two out of three domains should be present to establish a diagnosis of PCOS. These domains are: an-/oligo-ovulation, hyperandrogenism (clinical ± biochemical) and polycystic ovary morphology on ultrasound examination, with exclusion of other causes of hyperandrogenism (6). In 2012, the National Institute of Health reinforced the need for identification of four phenotypes within the Rotterdam criteria in women with PCOS, which refer to the combination of diagnostic criteria (7). By using the possible combinations of these criteria, four different phenotypes of PCOS are now identified: i. Hyperandrogenism (clinical or biochemical) and chronic anovulation (H-CA), ii. Hyperandrogenism and polycystic ovaries on ultrasound (PCOm), but with ovulatory cycles (H-PCOm), iii. Chronic anovulation and polycystic ovaries without hyperandrogenism (CA-PCOm), and iv. Hyperandrogenism, chronic anovulation and polycystic ovaries (H-CA-PCOm). The identification of specific phenotypes in women with PCOS seems to be justified from the metabolic point (3).
This heterogeneous condition manifests with many clinical presentations, including infertility, pregnancy complications, and psychological and metabolic features. The reproductive problems associated with PCOS consist mainly of menstrual dysfunction, infertility and pregnancy complications. Many treatments are proposed by different guidelines for infertility with PCOS, and include clomiphene citrate (CC), letrozole and gonadotrophins. However, there is a lack of clarity around the relative efficacy of these different treatments. Despite the agreement between most guidelines of the importance and priority of lifestyle modification in PCOS and weight loss, where women are overweight or obese, there are still limited studies that compare lifestyle modification and pharmacological drugs for reproductive outcomes (8). With regards to pharmacological treatment in isolation, CC is recommended as first-line treatment for ovulation induction (OI) in infertile women with POCS with the alternative treatment, letrozole, which has encouraging results in many recent trials (1,2,(8)(9)(10). Although the insulin sensitizer metformin has been recently recommended as a firstline treatment (11), its role and specific indication are controversial (1)(2)(3). The second-line treatment is usually recommended as gonadotrophins or laparoscopic ovarian drilling (LOD) (2). Additional issues relating to treatment of reproductive outcomes which are still somewhat controversial include the best time to use in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) in women who failed to become pregnant after pharmacological treatment, and the potential benefit of modern techniques like in vitro maturation (IVM) (2,3).
The aim of this review was to perform an overview to summarize and appraise the content, results and quality of systematic reviews that assess medical or surgical treat-ments for reproductive outcomes in women with PCOS.

Inclusion criteria
The Participant, Intervention, Comparison, Outcomes and Studies (PICOS) framework was used for this review. This overview is part of a larger overview of systematic reviews. For this broader overview, we included any systematic review or meta-analysis where the assessment or management of PCOS was the primary focus of the review, either as interventions in PCOS or a comparison of women with and without PCOS for a specific outcome. Exclusion criteria were studies where PCOS was a secondary condition assessed as part of a broader topic. For this specific overview, we included any systematic review that assessed the effect of medical or surgical management of PCOS on reproductive outcomes. The specific inclusion criteria were: i. Published from 2009 onwards, as this was the date of publication of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIS-MA) statement as a guideline for conducting systematic reviews (12), ii. Must have included a search strategy that contained at least key words or terms, iii. Must include the number of identified and included articles, and iv. The review needed to conduct some form of quality appraisal of the articles. The comparisons term was not applicable in this review context. The outcomes assessed were reproductive outcomes, specifically live birth, clinical pregnancy, miscarriage, ovulation, multiple pregnancy, menstrual cycle frequency, follicular size, pregnancy related outcomes (gestational diabetes, pregnancy-induced hypertension and pre-eclampsia), neonatal outcomes, costs and side effects. Only articles published in English were included. The protocol is registered in the International Prospective Register of Systematic Reviews PROSPERO (CRD42016052649). was additionally searched on the 15 th September 2017 using the key words "PCOS" or "polycystic ovary syndrome". In addition, experts in the field were asked to provide any potentially relevant studies for consideration. Two independent reviewers, who were not blinded to the names of investigators or sources of publication, identified and selected the articles that met the inclusion criteria (L.J.M, D.H or C.T.T). Disagreements between reviewers were discussed and resolved by consensus or arbitration with a third reviewer.

Data extraction
All eligible systematic reviews included were examined and extracted independently by two reviewers (L.J.M, M.G or C.T.T). Disagreements were discussed and resolved by consensus or arbitration with a third reviewer. The data extracted included information on author(s), year, country of author, inclusion criteria, study methodology, study outcomes, number of studies identified, number of participants in the review, whether a meta-analysis was conducted, and quality of identified articles in each review (as reported by the systematic review authors as overall quality of the entire study or evidence or reported as unclear if not summarized by the systematic review authors).

Data synthesis
A narrative description of the included reviews was performed. We presented results per reproductive outcome.

Quality assessment of systematic reviews
All included reviews were evaluated by two independent reviewers (L.J.M, M.G or C.T.T) using the Assessing the Methodological Quality of Systematic Reviews (AM-STAR) tool (13,14). Disagreements were discussed and resolved by consensus or arbitration with a third reviewer. The AMSTAR tool contains 11 items to appraise the methodological aspects of the systematic reviews. Each item was scored 1 for "yes" and 0 for "no" or "not applicable" with a total score range from 0 to 11. The methodological quality for each review was classified as low [≤ 3], moderate [4][5][6][7] and high [8][9][10][11] (15) .
The meta-analyses reported statistically significant results for higher live birth, pregnancy and ovulation after letrozole compared to CC followed by timed intercourse in overall women with PCOS, and higher live birth and pregnancy after letrozole in women with PCOS and body mass index (BMI) >25 kg/m 2 (20,27,39,49). In women with CC resistance, letrozole with or without metformin resulted in higher live births compared to CC with metformin (32,39), letrozole resulted in higher pregnancy and ovulation than anastrozole and higher ovulation than LOD (49). Long-term letrozole (10 days) resulted in higher pregnancy than short-term letrozole (5 days) (Tables 1, 2) (49).  Reproductive Outcomes in PCOS
The meta-analyses reported in overall women with PCOS that CC compared to placebo had statistically higher pregnancy and ovulation (46). Early follicular CC had higher pregnancy than late luteal CC (46) but with less mature follicles (36). Higher live birth, pregnancy, and ovulation resulted after CC compared to metformin mainly in women with BMI ≥30 kg/m 2 (28, 30, 41) while metformin resulted in higher pregnancy than CC in women with BMI <30 kg/m 2 (41). CC plus metformin was of more benefit than CC or metformin alone with regards to live birth (24), pregnancy and ovulation, but had higher gastrointestinal side effects (24,28,30,33,41). Higher live birth and pregnancy resulted after gonadotrophins compared to CC and 10 days of CC compared to 5 days of CC, respectively (46).
In women with CC resistant PCOS, gonadotrophins resulted in statistically higher live birth, pregnancy and ovulation than CC plus metformin (32,46) which, in turn, resulted in higher live birth than LOD (19). In the same population of women, the addition of dexamethasone, NAC or contraceptive pills to CC resulted in higher live births, pregnancy and ovulation than CC alone (46,47). Furthermore, the addition of metformin to CC resulted in more favourable outcomes compared with the addition of NAC with regards to pregnancy and ovulation. However, the cost of treatment was greater for gonadotrophins followed by LOD then CC plus metformin (19).
The meta-analyses reported that in women with CC resistant PCOS, gonadotrophins resulted in statistically higher live births, multiple pregnancies, and costs of short-and long-term treatment in comparison to LOD (19,23) and higher live births, pregnancy and ovulation in comparison to CC ± metformin (32,46), but lower pregnancy in comparison to letrozole (39). Adding metformin to gonadotrophins, compared to gonadotrophins alone, resulted in higher live birth and pregnancy in OI (40,45) and higher live birth, implantation rate, lower miscarriage, ovarian hyperstimulation syndrome (OHSS) and number of oocyte retrieved in IVF (59). Recombinant follicle stimulating hormone (FT.) resulted in lower dose and stimulation duration than other urinary gonadotrophins in OI (29).

Reproductive Outcomes in PCOS
The meta-analyses reported that, overall in women with PCOS, metformin resulted in higher live births, pregnancy, and gastrointestinal side effects with lower OHSS than placebo when used in addition to IVF (18,21,42) and higher pregnancy, ovulation, side effects and menstrual frequency in OI (41). Metformin had higher gastrointestinal side effects than thiazolidinediones (22). In women with CC resistant PCOS, NAC resulted in higher live births, pregnancy and ovulation than placebo, but lower pregnancy and ovulation than metformin (47). Oral contraceptive pills were better than metformin in improving menstrual frequency (34). Adding vitamin D to metformin improved menstrual frequency than metformin alone (37). Inositol resulted in higher pregnancy than placebo with more benefit of myoinositol over D-chiro inositol in IVF (18), while inositol resulted in higher ovulation than placebo in OI. Roziglitaone, pioglitazone and inositol improved menstrual frequency in OI (38). In women with PCOS who became pregnant, metformin intake during pregnancy resulted in higher live birth and lower miscarriage, preterm labour, gestational hypertension, preeclampsia, gestational diabetes and intrauterine growth retardation (52)(53)(54)58).
The meta-analyses reported that LOD resulted in lower live births than CC plus metformin and gonadotrophins, respectively (19,23), higher pregnancy than metformin alone (19), lower ovulation than letrozole (49), higher costs than CC plus metformin but lower than gonadotrophins (19) and lower multiple pregnancy rate than other medical treatments (19). Pregnancy and ovulation were higher in lean women (BMI <25 kg/m 2 ) with CC resistant PCOS than in overweight and obese women (BMI ≥25 kg/m 2 ) undergoing LOD (56).

Intrauterine insemination, in vitro fertilization, intracytoplasmic sperm injection related interventions
Nine reviews [three high quality (17,18,42)] and six moderate quality (21,26,31,50,57,59) assessed different interventions in women with PCOS undergoing assisted reproductive techniques [intrauterine insemination (IUI), IVF/ICSI] comprising 126 trials with 12 298 participants in eight reviews and 333 cycles in the ninth review which did not report on the number of participants (57). Three reviews assessed gonadotrophin releasing hormone (GnRH) antagonist as an adjuvant intervention in controlled ovarian stimulation plus IUI (57) and in comparison with GnRH agonist during IVF/ICSI (26,31). Three reviews assessed the effect of metformin during IVF/ICSI (21,42,59). Two reviews assessed the use of IVM (17,50).

Other interventions
A low quality review reported that bariatric surgery improved menstrual frequency in women with PCOS in six trials and 264 participants (51). A high quality review reported that statins did not improve menstrual frequency or ovulation in women with PCOS not trying to conceive in four trials and 244 participants (43). A high quality review (44) assessed the use of antidepressants in women with PCOS, and identified no studies reporting on any of the primary reproductive outcomes with the exception of one RCT that reported on endocrine and metabolic outcomes between fluoxetine with sibutramine found no significant difference between both drugs (61). A moderate quality review assessed orlistat versus other anti-obesity drugs and found no difference in reproductive outcomes (55).

Discussion
We reported the first overview of systematic reviews on treatment for reproductive outcomes in women with PCOS. This review follows a process of systematic reviews proposed by the Cochrane collaboration that sum-marizes evidence from more than one systematic review of different interventions for the same condition (62,63). This type of review can be utilized as a rich source of data synthesis for developing and updating guidelines, and for health care policy makers. Our overview included 53 systematic reviews (9 older versions and 44 currently updated articles), 498 studies, and 56 057 participants. The quality of most included reviews was moderate to high, although the quality of included studies was variable.
Our results align with most current guidelines on PCOS. According to many guidelines, treatment of anovulation in PCOS should start with lifestyle modification before commencing pharmacological agents, especially in obese women with BMI >30 kg/m 2 (1, 3, 8, 10, 11), The firstline pharmacological agent is usually CC (2,3,11,64,65) and some guidelines propose letrozole as an alternative (1,8,10). Our results suggest that, overall, in women with PCOS (with or without CC resistance), letrozole resulted in higher live birth and clinical pregnancy rates than other OI drugs, especially CC. This is consistent with many reviews and RCTs (9,20,27,32,39,49,(66)(67)(68), despite the fact that letrozole is an off-label drug in OI. Nevertheless, the issue of safety in pregnancy for both CC and letrozole has not been completely resolved. Most large retrospective studies found no evidence of any difference between these drugs (69). Metformin is recommended in many guidelines as an adjunctive treatment with CC in women with glucose intolerance and in obese women (1-3, 8, 10), while the National Institute for Health and Clinical Excellence Guidance (NICE) recommended metformin alone or with CC as a first-line treatment (11). Our results suggest that, overall, in women with PCOS, CC plus metformin also resulted in in better reproductive outcomes than CC or metformin alone. The Australian National Health and Medical Research Council (NHMRC) evidence-based guidelines suggested that it is acceptable to use gonadotrophins as a first-line treatment (8). Our results suggest that the use of gonadotrophins resulted in higher live birth and clinical pregnancy rates than CC, overall, in women with PCOS.
CC is usually used for six months, which is recommended by many guidelines (1,8,11). After that, women are considered to be CC resistant, which necessitates a second-line treatment. Most fertility guidelines recommend low dose gonadotrophins or LOD as a second-line treatment (1-3, 8, 10, 11). CC plus metformin was also recommended by some guidelines, if not already used as a first-line treatment (8,11). Gonadotrophins have the disadvantage of cost and increased rates of multiple pregnancies, while LOD has a risk with anaesthesia, decreased ovarian reserve, and the need to use adjuvant drugs for OI after surgery (3). Our results suggest that, in women with CC resistant PCOS, gonadotrophins resulted in better reproductive outcomes than many OI drugs with the disadvantages of increased multiple pregnancies and increased cost (19,23,32,46). We found that women who used gonadotrophins had higher live birth than those who were prescribed CC plus metformin or LOD respectively, and higher clinical pregnancy and ovulation rates than CC plus metformin. CC plus metformin resulted in higher live birth rate and lower cost than LOD. Gonadotrophins are more expensive than LOD. LOD has the advantage of lower rates of multiple pregnancies compared to other interventions, such as gonadotrophins, in CC resistant PCOS (19). LOD in lean women seem to have better reproductive outcomes than in overweight and obese women.
Current recommendations state that IVF should be used in case of CC failure, which is defined by failure of conception after 6-9 months (1,11). Our results support the current evidence for use of GnRH antagonists and addition of metformin to GnRH agonist to decrease OHSS (1). There is lack of data on use of IVM in PCOS (1), which is reported by one of included reviews (17). Another review by the same author reported higher pregnancy and implantation rates with lower cancellation rate in women with PCOS undergoing IVM compared to IVM in non-PCOS women (50).
Despite the large number of reviews and RCTs that have been conducted assessing different treatments for management of reproductive outcomes in women with PCOS, there are still a considerable number of research gaps. Recently, the international evidence-based guideline for the assessment and management of PCOS has issued new recommendations for the diagnosis and management of PCOS (70). These guidelines state that letrozole should be considered first-line pharmacological treatment for OI in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation, pregnancy and live birth rates. This is consistent with our results in this overview. They also stated that inositol (in any form) should currently be considered an experimental therapy in PCOS, with emerging evidence on efficacy highlighting the need for further research (70). Furthermore, research on the possible reasons for CC resistance and failure utilizing unified definitions is needed. This is particularly relevant given that some recent reviews revealed that the antiestrogenic effect of CC, specifically on endometrial tissue, is not enough rationale for resistance and failure (66). Furthermore, a recent crossover RCT found that there is no difference in clinical pregnancy and live birth rates between CC and letrozole when used as a second line treatment in women who failed to ovulate or conceive with CC or letrozole as first line of treatment (9). It is also important to note that a thorough study of the cost effectiveness of any of these treatments has not been performed, particularly in low income countries. Further investigation of metformin with regards to its cost effectiveness, safety, and effectiveness in non-obese women is also needed (1,8). There is also a lack of data relating to the comparison between the use of LOD and medical treatment as a first line treatment, and the minimum efficient dose of LOD to induce ovulation without affecting ovarian reserve (1,3,11).
Limitations include our search strategy with reviews pub-Reproductive Outcomes in PCOS lished from 2009 onwards, coinciding with the PRISMA statement publication for conducting systematic reviews. While this would miss earlier reviews, later included reviews would be likely to be of higher quality and aligned with the PRISMA statement. We applied language restrictions including only articles in English, which might lead to bias in exclusion of other languages. We found insufficient data on the quality of included studies in each review. We did not perform a quality assessment of each of the individual trials within each systematic review and relied instead on the judgement of the authors which varied from cursory to comprehensive; although we note that performing a quality assessment of 498 total studies would have been an extensive task. We note that the actual effect of different treatments in each treatment status and PCOS phenotypes is still unclear. We also note wide variability in the definition of outcomes across reviews and included studies. For instance, although pregnancy was reported as clinical pregnancy in most included reviews, ongoing pregnancy was reported in some reviews (26,45) and pregnancy was not predefined in others (22,24,36,40,51,56). The definition of clinical pregnancy varied across the included studies within each review.

Conclusion
We report here a significant contribution to the literature in the overview and synthesis of systematic reviews that assessed medical and surgical treatments for reproductive outcomes in women with PCOS. In agreement with most recent international guidelines on management of PCOS, letrozole was superior to other OI agents as a first-line pharmacological treatment with gonadotrophins a second-line pharmacological treatment for anovulatory women with PCOS.